Nr-CAM is a target gene of the β-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis

Conacci‐Sorrell, Maralice; Ben-Yedidia, Tamar; Shtutman, Michael; Feinstein, Elena; Einat, Paz; Ben-Ze’ev, Avri

doi:10.1101/gad.227502

Cited by 172 publications

(143 citation statements)

References 67 publications

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“…Several genes important for migration and proliferation in normal colonic epithelium at the top of the crypts and as well as in colon carcinoma are known to be controlled by the LEF/TCF family of transcription factors. [24][25][26][27][28][29][30][31][32] Here, we could identify MTAP as one further gene upregulated during epithelialmesenchymal transition. Interestingly, in other cell types tested no induction of MTAP promoter activity by cotransfection of LEF-1, TCF-1 or TCF-4 was found.…”

Section: Discussionmentioning

confidence: 99%

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Bataille

Rogler

Modes

et al. 2005

Laboratory Investigation

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Methylthioadenosine phosphorylase (MTAP) is known as a ubiquitously expressed house keeping gene important in biochemical salvage processes. The MTAP gene is localized on the human chromosomal region 9p21, a region often deleted in cancer. Recently, several groups including our own have shown that MTAP serves as a tumour suppressor gene. The aim of this study was to analyse the role of MTAP in colon carcinoma and normal colon epithelium and the regulation of gene expression. To examine MTAP RNA and protein expression, we screened six colon carcinoma cell lines and human primary colon epithelial cells by RT-PCR and immunoblotting. MTAP expression was confirmed in vivo by immunohistochemical staining of normal colon tissue compared to adenoma and colon carcinoma. Interestingly, we found strong MTAP mRNA and protein expression by colon carcinoma cell lines but no expression by colonic epithelial cells. To analyse the regulation of MTAP expression, promoter studies were performed and revealed control of MTAP expression by LEF/TCF/bcatenin. Furthermore, we demonstrated a significant correlation between MTAP protein expression and tumour progression as the intensity of MTAP protein staining increased from normal tissue to carcinoma. In addition, the recently postulated association between MTAP activity and interferon (IFN) sensitivity was confirmed in colon epithelial cells showing only little response to IFN-gamma, in contrast to the carcinoma cell lines. In summary, these data indicate for the first time that MTAP is not expressed in normal human colonic epithelium but is strongly upregulated in colon carcinoma. This finding may be of clinical significance concerning the homeostasis of normal colon epithelium and potential treatment of colon carcinoma. Laboratory Investigation ( 2.28) plays a major role in polyamine metabolism and is important for the salvage of both adenine and methionine. MTAP catalyses the phosphorylation of methylthioadenosine (MTA), a by-product of the synthesis of polyamines, which acts as a potent inhibitor of polyamine aminopropyltransferase and methyltransferases. MTAP has been shown previously to be expressed abundantly in normal cells and tissues. 1 In contrast, many malignant cells lack MTAP activity, 2-5 and cultured MTAP-deficient cells secrete MTA instead of metabolising it. 6 The reason for the frequent loss of MTAP activity became evident after determining the chromosomal location of MTAP. Starting from the centromeric end, the gene order on human chromosome 9p21 was mapped as p15-p16-MTAP-interferon(IFN)-alpha-IFNbeta. 1 In this region, many tumours reveal selective deletions. Recently, MTAP gene deletions were described in endometrial cancer, osteosarcoma and in haematological neoplasias like lymphoblastic leukaemia or non-Hodgkin's lymphomas. [2][3][4][5] In addition to its role in polyamine metabolism, MTAP expression has recently been shown to have significant impact on signal transducer and activator of transcription (STAT) 1 activity. 7 STAT1 is

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Section: Discussionmentioning

confidence: 99%

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Bataille

Rogler

Modes

et al. 2005

Laboratory Investigation

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“…L1CAM family members L1, CHL1, and NrCAM have been annotated roles in cancer progression and metastasis, and are involved in the regulation of proliferation and migration of diverse cancer types 5, 7, 11, 18, 19, 20, 23, 28…”

Section: Discussionmentioning

confidence: 99%

Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer

Erdem

Arnoldussen

Skaug

et al. 2017

Molecular Carcinogenesis

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Metastasis and cell adhesion are key aspects of cancer progression. Neurofascin (NFASC) is a member of the immunoglobulin superfamily of adhesion molecules and, while studies on NFASC are inadequate, other members have been indicated pivotal roles in cancer progression and metastasis. This study aimed at increasing the knowledge on the involvement of adhesion molecules in lung cancer progression by studying the regulation and role of NFASC in non‐small cell lung cancer (NSCLC). Here, copy number variations in the NFASC gene were analyzed in tumor and non‐tumorous lung tissues of 204 NSCLC patients. Frequent gene amplifications (OR = 4.50, 95%CI: 2.27‐8.92, P ≤ 0.001) and increased expression of NFASC (P = 0.034) were identified in tumors of NSCLC patients. Furthermore, molecular mechanisms of NFASC in lung cancer progression were evaluated by investigating the effects of NFASC silencing on cell proliferation, viability, migration, and invasion using siRNA technology in four NSCLC cell lines. Silencing of NFASC did not affect cell proliferation or viability but rather decreased NSCLC cell migration (P ≤ 0.001) and led to morphological changes, rearrangements in the actin cytoskeleton and changes in F‐actin networks in migrating NSCLC cell lines. This study is the first to report frequent copy number gain and increased expression of NFASC in NSCLC. Moreover, these data suggest that NFASC is a novel regulator of NSCLC cell motility and support a role of NFASC in the regulation of NSCLC progression.

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“…Examples include the scaffolding protein homer-2a/cupidin (Cluster 8) that links together critical components of the cell migration machinery, cell adhesion molecule NrCAM (Cluster 8) and calciumbinding protein calcyclin (Cluster 7) (Shiraishi et al, 1999;Bug et al, 2002;Conacci-Sorrell et al, 2002). Antisense knockdown of NrCAM and calcyclin has been demonstrated to reduce glioblastoma cell and lung fibroblast proliferation, respectively (Sehgal et al, 1999;Breen and Tang, 2003).…”

Section: Discussionmentioning

confidence: 99%

Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12

Teramoto

Castellone

Malek³

et al. 2004

Oncogene

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Activated forms of Ras family members are prevalent in many cancers where Ras mutants transduce signals essential for transformation, angiogenesis, invasion and metastasis. As a cancer progression model, we used NIH3T3 cells to explore the mechanism of Ras-induced tumorigenesis. Ras family mutants H-RasV12 and Rit79L strongly induced foci formation, while Rho family mutants RhoA-QL, Rac1-QL and Cdc42-QL were less effective. A comparison of downstream transcriptional targets of Ras and Rho family members using a 26 383 element cDNA microarray revealed that the osteopontin (OPN) gene exhibited the best correlation between magnitude of gene expression change and level of foci formation (r ¼ 0.96, Po0.001). In association with H-RasV12-and Rit79L-mediated transformation, foci secreted OPN protein and upregulated the OPN receptor CD44, suggesting the novel initiation of an aberrant OPN-CD44-Rac autocrine pathway. In support of this were the following observations. First, RGD-deficient OPN protein-binding activity was present in H-RasV12-transformed cells but not in control cells, and binding activity was inhibited by the CD44 blocking antibody. Second, foci formation, cell invasion and Rac activity were induced by H-RasV12 and inhibited by the CD44 blocking antibody. Third, foci formation by H-RasV12 was substantially reduced by a short interfering RNA (siRNA) specifically targeting OPN expression for knockdown. Fourth, H-RasV12-mediated transformation was not blocked by the GRGDS peptide, suggesting that OPN effects were not mediated by the integrins. Lastly, OPN knockdown affected the downstream expression of 160 '2nd tier' genes, and at least a subset of these genes appears to be involved in transformation. Indeed, four genes were selected for knockdown, each resulting in a disruption of foci formation and/or invasion. These results underscore the role of aberrant autocrine signaling and transcriptional networking during tumorigenesis.

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Nr-CAM is a target gene of the β-catenin/LEF-1 pathway in melanoma and colon cancer and its expression enhances motility and confers tumorigenesis

Cited by 172 publications

References 67 publications

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Strong expression of methylthioadenosine phosphorylase (MTAP) in human colon carcinoma cells is regulated by TCF1/[beta]-catenin

Copy number variation, increased gene expression, and molecular mechanisms of neurofascin in lung cancer

Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12

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